Chronic inflammatory disease is characterized by chronic, or persistent, inflammation. Chronic inflammatory disease encompasses a large number of diseases, many of which comprise a genetic component. Specifically, many chronic inflammatory diseases are caused by a subject's genetic predisposition for developing the disease. Furthermore, the predisposition for developing certain chronic inflammatory diseases is caused by interaction and/or expression of multiple genes.
Chronic inflammatory disease can develop as a result of a patient's exposure to harmful stimuli. For example, exposure to certain foods and environmental factors may trigger the development of chronic inflammatory disease. Chronic inflammatory disease can result in pain, fatigue, and digestive problems. Furthermore, the chronic nature of the inflammation may lead to tissue damage which can lead to a variety of additional problems. For example, chronic inflammation in the liver and digestive tract can lead to neurological changes such as fatigue and changes in personality. Chronic inflammation can also alter normal function of organs which can cause systemic disease and disorders in afflicted patients.
Examples of chronic inflammatory disease include celiac disease, vasculitis, lupus, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, atherosclerosis, arthritis, and psoriasis. Specifically, inflammatory bowel disease is a broad class of chronic inflammatory diseases. Examples of inflammatory bowel diseases are Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's disease, indeterminate colitis. While many of these diseases have genetic components, the specific triggers and underlying biochemical causes for the onset of the diseases remain unknown. Furthermore, because the triggers and underlying biochemical causes of the diseases remain largely unknown, treatment regimes merely target reducing the symptoms without eliminating the disease or the chronic inflammation entirely.
Because the inflammation is not easily controlled, constant medication is often administered to lessen the symptoms and side effects of the inflammation. The medications often include antibiotics, aminosalicylates, corticosteroids, immune modifiers, and biologic therapies. However, the medication will often lead additional pain such as aching joints and headache, fatigue, digestive problems, fever, skin irritation and sensitivity, stomach pain and irritation, dizziness, increased blood pressure, fluid retention, cataracts, glaucoma, high blood sugar, increased risk of infection, osteoporosis, weak bones, suppressed adrenal gland hormone production, and increased risk of bruising and bleeding. Accordingly, even though the inflammation may lessen and worsen throughout the course of the chronic disease with the aid of medical therapies, it is often very difficult to treat and persists with most known treatment regimes.
Recently, genetic studies have begun to elucidate factors contributing to chronic inflammatory disorders. For example, mucosal innate lymphocyte subsets have emerged as an important new factor in multiple chronic inflammatory disorders, including Crohn's Disease (CD). Furthermore, a recent genetic study identified the killer cell immunoglobulin-like receptor (KIR) gene KIR2DL2/3 of natural killer (NK) cells in the context of its ligand human leukocyte antigen (HLA)-C1 as a risk factor for CD. However, the cellular mechanism of this genetic contribution is unknown. Accordingly, without knowing the cellular mechanism of the genetic contribution of the KIR genes, the ability to customize therapies to such chronic inflammatory diseases and predict the effectiveness of a therapy remains unknown. Furthermore, without customized therapies and predicted efficacy of the therapies is known, constant medication (e.g., antibiotics, aminosalicylates, corticosteroids, immune modifiers, and biologic therapies) remains a necessity and negative side effects of the medications will continue to be problematic for patients.
This invention describes the ‘licensing’ of natural killer (NK) cells by specific genetic combinations of KIR and HLA genes results in their functional reprogramming, and permits them to promote CD4+ T cell activation and TH17 differentiation ex vivo. Multiplexed bulk and single cell analysis of cytokine profile established that genetically licensed NK cells had a distinct cytokine profile from unlicensed NK cells, including polarized production of interferon (IFN)-y, tumor necrosis factor (TNF)-α, chemokine (C—C motif) ligand (CCL)-5, and macrophage inflammatory protein (MIP)-1β. These functional attributes of licensed NK cells were genetically rather than disease-defined, as they were observed in genetically licensed cohorts of healthy subjects, CD patients, and multiple sclerosis (MS) patients. Licensed NK cytokines augmented CD4+ T cell proliferation and interleukin (IL)-17A/IL-22 production. Antibody blocking indicated a primary role for IFN-y, TNF-α, and IL-6 in the augmented T cell proliferative response. Thus, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel NK cytokine program that activates and induces pro-inflammatory CD4+ T cells, thereby providing a biologic mechanism for KIR-associated susceptibility to CD and other chronic inflammatory diseases.